Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: a meta-analysis with trial sequential analysis of randomized controlled trials

Abstract

Background: Regional citrate or heparin is often prescribed as an anticoagulant for continuous renal replacement therapy (CRRT). However, their efficacy and safety remain controversial. Therefore, we performed this meta-analysis to compare these two agents and to determine whether the currently available evidence is sufficient and conclusive by using trial sequential analysis (TSA).

Methods: We searched for relevant studies in PubMed, Embase, the Cochrane Library databases and the China National Knowledge Infrastructure (CNKI) Database from database inception until September 2015. We selected randomized controlled trials comparing regional citrate with heparin in adult patients with acute kidney injury (AKI) who were prescribed CRRT.

Results: Fourteen trials (n = 1134) met the inclusion criteria. Pooled analyses showed that there was no difference in mortality between the regional citrate and heparin groups (relative risk (RR) 0.97, 95 % confidence interval (CI) 0.84, 1.13, P > 0.05), which was confirmed by TSA. Compared with heparin, regional citrate significantly prolonged the circuit life span in the continuous venovenous haemofiltration (CVVH) subgroup (mean difference (MD) 8.18, 95 % CI 3.86, 12.51, P < 0.01) and pre-dilution subgroup (MD 17.51, 95 % CI 9.85, 25.17, P < 0.01) but not in the continuous venovenous haemodiafiltration (CVVHDF) subgroup (MD 28.60, 95 % CI -3.52, 60.73, P > 0.05) or post-dilution subgroup (MD 13.06, 95 % CI -2.36, 28.48, P > 0.05). However, the results were not confirmed by TSA. A reduced risk of bleeding was found in the regional citrate compared with the systemic heparin group (RR 0.31, 95 % CI 0.19, 0.51, P < 0.01) and TSA provided conclusive evidence. Fewer episodes of heparin-induced thrombocytopoenia (HIT) (RR 0.41, 95 % CI 0.19, 0.87, P = 0.02) and a greater number of episodes of hypocalcaemia (RR 3.96, 95 % CI 1.50, 10.43, P < 0.01) were found in the regional citrate group. However, TSA did not provide conclusive evidence.

Conclusion: In adult patients with AKI, there is no difference in mortality between the regional citrate and heparin treated groups. However, regional citrate is more efficacious in prolonging circuit life span and reducing the risk of bleeding and should be recommended as the priority anticoagulant for critically ill patients who require CRRT.

Keywords: Anticoagulation; Continuous renal replacement therapy; Heparin; Meta-analysis; Regional citrate; Trial sequential analysis.

Fig. 1

Flow chart of the study selection. CNKI Chinese National Knowledge Infrastructure

Fig. 2

Assessment for risk of bias. NL The Netherlands, AU Australia, CN China, DE Germany, CA Canada, BE Belgium, CH Switzerland, TH Thailand

Fig. 3

Effect of regional citrate versus heparin anticoagulation on mortality. a Mortality. b Fixed-effect model of trial sequential analysis for mortality. A diversity-adjusted information size of 1021 participants calculated on the basis of a mortality rate of 42.66 % in the heparin group, relative risk reduction 20 %, α = 5 % (two sided), β = 20 %, I ² = 0 %. Complete blue line represents cumulative Z-curve, which crossed the futility boundary (complete red line) and reached the futility area. AU Australia, DE Germany, CA Canada, NL The Netherlands, CH Switzerland, M-H Mantel-Haenszel

Fig. 4

Effect of regional citrate versus heparin anticoagulation on circuit life span (continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF) subgroup analysis). a Circuit life span. b-g Complete blue line represents the cumulative Z-curve, complete red line represents the trial sequential monitoring boundary for benefit and etched green line represents the conventional boundary for benefit. b The DerSimonian-Laird (DL) approach used for all trials. A diversity-adjusted information size of 1219 circuits was calculated on the basis of a mean difference (MD) of 15.43, variance of 167.21, I ² = 98.11 %, α = 5 % (two sided) and β = 20 %. Cumulative Z-curve crosses the trial sequential monitoring boundary for benefit and reaches the required information size. c The Sidik-Jonkman (SJ) approach used for all trials. A diversity-adjusted information size of 5196 circuits was calculated on the basis of a MD of 17.14, variance of 167.21, I ² = 99.65 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve crosses the conventional boundary for benefit but not the trial sequential monitoring boundary for benefit. d The DL approach used for the CVVH subgroup. A diversity-adjusted information size of 1033 circuits was calculated on the basis of a MD of 8.18, variance of 110.0, I ² = 94.97 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve crosses both the conventional boundary and the trial sequential monitoring boundary. e The SJ approach used for the CVVH subgroup. A diversity-adjusted information size of 3851 circuits was calculated on the basis of a MD of 11.08, variance of 110.0, I ² = 99.25 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve crosses the conventional boundary, but not the trial sequential monitoring boundary. f, g The DL and SJ approaches used for the CVVHDF subgroup. The cumulative Z-curve does not cross the conventional boundary or the trial sequential monitoring boundary. NL The Netherlands, CN, China, AU Australia, DE Germany, BE Belgium, IV Inverse Variance

Fig. 5

Effect of regional citrate versus heparin anticoagulation on circuit life span (pre-dilution and post-dilution subgroup analysis). a Circuit life span. b-e Complete blue line represents the cumulative Z-curve, complete red line represents the trial sequential monitoring boundary for benefit and etched green line represents the conventional boundary for benefit. b The DerSimonian-Laird (DL) approach used for the pre-dilution subgroup (eight trials). A diversity-adjusted information size of 1355 circuits was calculated on the basis of a mean difference (MD) of 17.51, variance of 150.43, I ² = 98.82 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve crosses the trial sequential monitoring boundary for benefit and reaches the required information size. c The Sidik-Jonkman (SJ) approach used for the pre-dilution subgroup (six trials: two trials ignored in the interim looks due to too low information use (<1.0 %)). A diversity-adjusted information size of 7106 circuits was calculated on the basis of a MD of 18.55, variance of 150.43, I ² = 99.8 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve crosses the conventional boundary but not the trial sequential monitoring boundary. d The DL approach used for the post-dilution subgroup (three trials). A diversity-adjusted information size of 2232 circuits was calculated on the basis of a MD of 13.06, variance of 509.29, I ² = 95.79 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve does not cross the conventional boundary or trial sequential monitoring boundary. e The SJ approach used for the post-dilution subgroup (two trials: one trial ignored in the interim looks due to too low information use (<1.0 %)). A diversity-adjusted information size of 6516 circuits calculated on the basis of a MD of 15.76, variance of 509.29, I ² = 99.0 %, α = 5 % (two sided) and β = 20 %. The cumulative Z-curve does not cross the conventional boundary or trial sequential monitoring boundary. AU Australia, DE Germany, CA, Canada, CN, China, NL The Netherlands, IV Inverse Variance